The 2006 survey of biopharmaceutical companies’ views of FDA oversight released last month yielded puzzling and worrisome results. The study, by a biotechnology industry group and a major consulting firm, generally has been spun as portraying the regulatory environment as favorable and improving. Most news reports noted, for example, that 81% of the surveyed companies said the FDA was performing better since the 1997 advent of user fees—another name for a discriminatory tax—intended to speed up product reviews. They ignored, however, that more than one-third of companies complained that the FDA had changed its position in the middle of the testing of a product. Also, more than half said that the FDA needs the most improvement in risk-based decision making, which is supposed to be its most essential stock in trade.

Without exception, no news report on the survey mentioned its methodological problems including the possibility of significant sampling errors: responders who were apparently self-selected represent fewer than 5% of biopharmaceutical companies; about half of the responders are based abroad; and a disproportionately small number of responders had drugs that had the FDA’s fast track or orphan drug designations (indicating that they were an atypical group).

Even if the current milieu is better than a decade ago (which, for the reasons discussed below, is doubtful), the trends are ominous. In spite of increasingly more powerful and precise technologies for drug discovery, purification, and production during the past 20 years, development costs have skyrocketed. According to the latest data (2006) from the Tufts Center for the Study of Drug Development, on average it takes more than eight years and costs $1.2 billion to develop a biopharmaceutical. Of this amount, capitalized out-of-pocket preclinical costs are approximately $615 million, while clinical testing accounts for $626 million.

Regulatory Issues

Why the huge costs and lengthy development times that exceed even those for conventional drugs? Regulatory excesses, for the most part. Regulators are inflexible and inconsistent and keep raising the bar for approval, especially for innovative, high-tech products.

Several highly publicized events have heightened public and congressional concern about drug safety during the past few years: inadequate warnings on the labels of antidepressants and the discovery of previously unknown adverse reactions to NSAIDs and the multiple sclerosis drug Tysabri.

However, contrary to perceptions that regulatory oversight might have become lax, drug regulation in the U.S. in recent years has actually become progressively more risk averse, as the FDA has steadily made it more difficult to initiate and perform clinical testing of new drugs.

Recent criticism from Congress, the media, and others regarding drug safety has caused an already risk-averse agency to become even more conservative and defensive in its decision making. The FDA has been requiring ever larger numbers of patients in clinical trials. Its demands for postmarketing clinical trials have proliferated wildly. Also, risk-management plans for newly approved drugs have been inconsistently applied, punitive, and often more appropriate for weapons-grade plutonium than prescription drugs.

Regulators moving the goalposts in the middle of the game is particularly vexing for drug developers. In September 2006, Genentech announced that approval of its colon cancer drug, Avastin, for breast cancer would be delayed at least one year because of requests from the FDA for additional data. The company said that regulators appeared to be increasing the stringency of requirements for certain types of clinical trials and had arbitrarily demanded that its trials be “audited and summarized” in a way different from that agreed upon earlier with regulators.

Another recent and particularly problematic example involves Somaxon Pharmaceuticals’ testing of an already-approved drug, doxepin, for a new indication. The drug, approved for the treatment of depression since 1969, is being tested in very low doses for use as a sleeping pill. FDA initially assured the company that it could begin clinical trials without first doing animal tests because of doxepin’s long history of use in people and because Somaxon was using a dose less than one-tenth of that used to treat depression.

In May 2006, however, after having completed several clinical trials, while the company was meeting with the FDA to discuss the submission of an NDA, regulators unexpectedly asked for a full battery of testing in animals.

European Drugs

A number of drugs previously granted marketing approval in Europe have received approvable, instead of approval, letters from the FDA, meaning that additional data is required before the drug can be marketed. These include sanofi-aventis’ Acomplia for weight loss and cessation of smoking, NPS Pharmaceuticals’ Preos for osteoporosis, and Encysive Pharmaceuticals’ Thelin for pulmonary hypertension.

Many new targeted therapies are difficult to assess with traditional clinical trial designs or endpoints. For example, a drug intended to arrest or eliminate cancer by boosting the patient’s immune system might be most efficacious in early-stage cancers when the tumor load is low and the patient is not debilitated. Thus, if the company were to adopt a clinical design that called for recruiting and treating only patients with advanced cancers, one would expect to see suboptimal efficacy.

This kind of situation, in which there is a high level of novelty and uncertainty, argues for greater flexibility both in clinical trial design and in reaching agreement on what constitutes efficacy. Instead, the FDA has been risk-averse and defensive, sometimes intransigent. In the review of cancer drugs in particular, FDA reviewers and managers frequently are characterized as inadequately prepared for meetings with industry scientists and insensitive to the needs of dying patients.

Times are tough for drug development, and they are getting worse. Beleaguered regulators are in a risk-averse, defensive mode. Congress has shirked its responsibility to ensure that innovation and ingenuity in drug development will flourish. If biopharmaceutical companies are not complaining loudly, we have seen the worst become the norm.

Henry I. Miller, M.D., is a fellow at Stanford University’s Hoover Institution. From 1989 to 1993
he was director of the FDA’s Office of Biotechnology.
E-mail: miller@hoover.stanford.edu.